Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials.

BACKGROUND: Patients with candidemia frequently have a central venous catheter (CVC) in place, and its early removal is considered the standard of care. METHODS: We performed a subgroup analysis of 2 phase III, multicenter, double-blind, randomized, controlled trials of candidemia to examine the effects of early CVC removal (within 24 or 48 h after treatment initiation) on the outcomes of 842 patients with candidemia. Inclusion criteria were candidemia, age >16 years, CVC at diagnosis, and receipt of 1 dose of the study drug. Six outcomes were evaluated: treatment success, rates of persistent and recurrent candidemia, time to mycological eradication, and survival at 28 and 42 days. Univariate and multivariate analyses were performed, controlling for potential confounders. RESULTS: In univariate analysis, early CVC removal did not improve time to mycological eradication or rates of persistent or recurrent candidemia but was associated with better treatment success and survival. These benefits were lost in multivariate analysis, which failed to show any beneficial effect of early CVC removal on all 6 outcomes and identified Acute Physiology and Chronic Health Evaluation II score, older age, and persistent neutropenia as the most significant variables. Our findings were consistent across all outcomes and time points (removal within 24 or 48 h and survival at 28 and 42 days). The median time to eradication of candidemia was similar between the 2 study groups. CONCLUSIONS: In this cohort of 842 adults with candidemia followed up prospectively, early CVC removal was not associated with any clinical benefit. These findings suggest an evidence-based re-evaluation of current treatment recommendations.

Treatment of candidemia and invasive candidiasis in the intensive care unit: post hoc analysis of a randomized, controlled trial comparing micafungin and liposomal amphotericin B.

INTRODUCTION: Invasive candidiasis and candidemia are life-threatening nosocomial infections in intensive care patients. METHODS: A post hoc analysis of a phase 3 trial assessing micafungin (100 mg/day for subjects > 40 kg; 2 mg/kg/day for subjects

Adjuvant corticosteroid therapy for chronic disseminated candidiasis.

BACKGROUND: Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia and requires protracted antifungal therapy. OBJECTIVE: Our objective was to document the efficacy and tolerance of corticosteroid therapy (CST) in patients with symptomatic CDC, including those who experienced fever and abdominal pain despite ongoing antifungal therapy. METHODS: We performed a retrospective, multicenter study involving 10 pediatric and adult patients who experienced ongoing symptomatic CDC despite receipt of appropriate antifungal therapy for whom adjuvant oral CST was initiated. RESULTS: All cases of CDC were proven or probable, as determined on the basis of the European Organization for Research and Treatment of Cancer-Mycosis Study Group definition criteria, and occurred in patients with leukemia. CDC-attributable clinical symptoms resolved with CST, which was started a mean of 33.8 days after antifungal therapy had been initiated. Fever and abdominal pain disappeared a median of 4-5 days, and serum fibrinogen and C-reactive protein levels returned to normal values within 14-30 days. The median duration of hospitalization after CST initiation was 8.8 days. Hepatosplenic microabscesses decreased or disappeared within a mean period of 107 days (range, 30-210 days). No relapses of CDC were observed during a median duration of follow-up of 6.5 years (range, 4-9 years). CONCLUSIONS: In children and adults who experience persistently symptomatic CDC despite ongoing receipt of antifungal therapy, CST involving a prednisone equivalent at a dosage of > or =0.5 mg/kg per day for at least 3 weeks is associated with a prompt resolution of symptoms and of inflammatory response. These findings support the pathophysiological hypothesis that CDC belongs to the spectrum of fungus-related immune reconstitution inflammatory syndrome.

Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Non-invasive, transdermal, path-selective and specific glucose monitoring via a graphene-based platform.

Currently, there is no available needle-free approach for diabetics to monitor glucose levels in the interstitial fluid. Here, we report a path-selective, non-invasive, transdermal glucose monitoring system based on a miniaturized pixel array platform (realized either by graphene-based thin-film technology, or screen-printing). The system samples glucose from the interstitial fluid via electroosmotic extraction through individual, privileged, follicular pathways in the skin, accessible via the pixels of the array. A proof of principle using mammalian skin ex vivo is demonstrated for specific and 'quantized' glucose extraction/detection via follicular pathways, and across the hypo- to hyper-glycaemic range in humans. Furthermore, the quantification of follicular and non-follicular glucose extraction fluxes is clearly shown. In vivo continuous monitoring of interstitial fluid-borne glucose with the pixel array was able to track blood sugar in healthy human subjects. This approach paves the way to clinically relevant glucose detection in diabetics without the need for invasive, finger-stick blood sampling.

Fungal internal carotid artery aneurysms: successful embolization of an Aspergillus-associated case and review.

BACKGROUND: Fungal aneurysms of the carotid artery are rare. We report here a case of Aspergillus fumigatus invasive sphenoidal sinusitis complicated by carotid artery aneurysms in a severely neutropenic patient who was successfully treated with a combination of antifungal therapy and embolization of all aneurysms. METHODS AND RESULTS: Carotid aneurysms were suspected when severe epistaxis occurred during follow-up for sinusitis. MRI angiograph and cerebral angiograph revealed 5 aneurysms involving the right intracavernous carotid artery. Coil endovascular embolization was successfully used for the first time in this context, and the patient is alive 2 years later. We also reviewed the literature and identified 10 cases of fungal carotid artery aneurysms. Aspergillus species was the most common fungal organism. All patients were immunocompromised and had to be treated surgically. CONCLUSIONS: Internal carotid arterial involvement is a rare but life-threatening complication of invasive fungal sinusitis. Fungal aneurysms should be diagnosed early, so that the embolization procedure can be performed before the occurrence of severe bleeding.

Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis.

BACKGROUND: Invasive candidiasis is an important cause of morbidity and mortality among patients with health care-associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. METHODS: This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. RESULTS: A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms. CONCLUSIONS: Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Balanced Ambipolar Organic Field-Effect Transistors by Polymer Preaggregation.

Ambipolar organic field-effect transistors (OFETs) based on heterojunction active films still suffer from an imbalance in the transport of electrons and holes. This problem is related to an uncontrolled phase separation between the donor and acceptor organic semiconductors in the thin films. In this work, we have developed a concept to improve the phase separation in heterojunction transistors to enhance their ambipolar performance. This concept is based on preaggregation of the donor polymer, in this case poly(3-hexylthiophene) (P3HT), before solution mixing with the small-molecular-weight acceptor, phenyl-C61-butyric acid methyl ester (PCBM). The resulting heterojunction transistor morphology consists of self-assembled P3HT fibers embedded in a PCBM matrix, ensuring balanced mobilities reaching 0.01 cm2/V s for both holes and electrons. These are the highest mobility values reported so far for ambipolar OFETs based on P3HT/PCBM blends. Preaggregation of the conjugated polymer before fabricating binary blends can be regarded as a general concept for a wider range of semiconducting systems applicable in organic electronic devices.

Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis.

Four HIV-1-infected patients presented with unusual clinical manifestations in the course of disseminated histoplasmosis, including liver abscesses, compressive lymphadenitis, intestinal obstruction, uveitis and arthritis within a median of 45 days after initiation of highly active antiretroviral therapy (HAART). They had a median increase of 106 CD4 cells/mul and granulomas with caseation in three. Partial immune reconstitution induced by HAART during disseminated histoplasmosis either related to the variety capsulatum or duboisii may be associated with immune reconstitution inflammatory syndrome.

Successful treatment of black-grain mycetoma with voriconazole.

Fungal mycetoma (or eumycetoma) are endemic diseases in tropical areas that have economic effects because of their chronic and disabling evolution. Classic treatments include surgery and antifungal drugs, but these have multiple side effects. We report a case of black-grain fungal mycetoma successfully treated with voriconazole without side effects. The duration of the treatment remains unclear, but must be prolonged because of the frequency of relapses.

[Use of topical antifungal agents]. / Utilisation des antifongiques topiques.

Topical antifungal agents are not absorbed when given orally. They act by direct contact on the fungus, this type of action requires the simultaneous presence of antifungal and fungus for a minimum of time. There are a large number of compounds belonging to different families of antifungals: polyens, azoles, allylamine and morpholine and antiseptic substances. The treatment of oropharyngeal candidiasis is based on topical antifungal agents: amphotericin B or nystatin, imidazoles such as clotrimazole or miconazole. Systemic antifungal agents are indicated in case or poor compliance to topical agents, in prophylaxis of highly relapsing disease, in oesophageal candidiasis and in Candida onychomycosis. A topical antifungal agent is the first choice to treat Candida intertrigo. In any case predisposing factors should be eradicated or amended. Infection to Malassezia spp. are treated topically with azoles or selenium sulphur. Oral ketoconazole is an alternative in severe cases. Dermatophytosis requires a systemic antifungal treatment such as terbinafine in chronic, dry, moccassin type palmoplantar infection and for onychomycosis. Intertrigo and tinea corporis are treated with topical agents such as azoles, terbinafine or tolnaftate. Tinea capitis responds to oral griseofulvine, however a topical antifungal must be added to eradicate contagious conidia. Whatever the localisation is, an other superficial site of infection must be looked for and a source of infection should be investigated and eradicated.

The quest for the shortest fragments of A (13-19) and B (12-17) responsible for the aggregation of human insulin.

AIM: To identify the shortest components of A13-A19, B12-B17 fragments capable for fibrillation and to validate the dependability of aggregation on the presence of hydroxyl group engaged in the 'tyrosine kissing'. MATERIALS & METHODS: Fragments A13-A19 and B12-B17 of insulin and all shortened analogues were obtained by using DMT/NMM/TosO(-) as a coupling reagent. The aggregation was studied by three independent tests. RESULTS: Studies on the susceptibility to aggregation of truncated analogs of insulin amyloidogenic core show three groups of peptides. CONCLUSION: Truncation of A13-A419 fragment shows that fibrous structures are formed by all peptides bearing (13)H-LeuTyr-OH(14). Propensity to aggregation was found for (16)H-TyrLeu-OH(17) B12-B17 fragment. Tyrosine residue modification by incorporation of tert-butyl group on hydroxyl function gave analogues still predisposed to aggregation.

Voriconazole for invasive bone aspergillosis: a worldwide experience of 20 cases.

UNLABELLED: BACKGROUND; Bone aspergillosis remains a rare but potentially devastating fungal disease. Although voriconazole is effective for invasive pulmonary aspergillosis, evidence of its efficacy for aspergillosis located in bone is limited. METHODS: We report our experience with voriconazole in 4 cases of invasive bone aspergillosis. In addition, all cases of probable and definite bone aspergillosis from the Pfizer clinical database were reviewed and analyzed to determine the safety and efficacy of voriconazole treatment. Global response was evaluated at the end of therapy on the basis of a composite assessment of overall clinical, radiological, and mycological responses. RESULTS: Twenty patients are described, of whom 18 had definite bone involvement diagnosed (spondylodiskitis in 9, sternum/rib osteomyelitis in 6, and peripheral bone involvement in 5). Of 20 patients, 14 were immunocompromised. Oral or intravenous voriconazole was given as salvage therapy for 18 patients; 2 patients received voriconazole as first-line therapy. Median duration of voriconazole treatment was 83.5 days (range, 4-395 days). Global response at end of therapy was satisfactory in 11 (55%) of 20 patients, including complete responses in 4 patients and partial responses in 7 patients; there were no relapses of infection in the 4 patients with complete response to therapy with voriconazole. Treatment was generally well tolerated. CONCLUSIONS: Long-term voriconazole treatment is a new therapeutic option for invasive aspergillosis with bone involvement.

Prevalence of mixed cryoglobulins in relation to CD4 cell count among patients coinfected with HIV and hepatitis C virus.

Cryoglobulinemia was studied in human immunodeficiency virus-positive, hepatitis C virus (HCV)-positive patients in relation to their CD4 cell count. Cryoglobulinemia was found in 18 (31.6%) of 57 patients: 17 (44.7%) of 38 patients with a CD4 cell count of >or=200 cells/ micro L versus 1 (5.3%) of 19 patients with a CD4 cell count of <200 cells/ micro L (P=.0064). Cell-mediated immunity could, therefore, contribute to the production of HCV-associated cryoglobulins.

Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras.

OBJECTIVE: To analyse the epidemiological evolution of cryptococcosis in France after the introduction of highly active antiretroviral therapy (HAART). DESIGN: Retrospective study of cryptococcosis cases recorded at the National Reference Center for Mycoses in France since 1985. METHODS: Using the national surveillance data, we reviewed 1644 cases of HIV-associated cryptococcosis diagnosed in France (population, 59 million) between 1985 and 2001 and compared them to 335 cases recorded in HIV-negative patients. RESULTS: The total number of cryptococcosis cases evolved in parallel to that recorded for HIV-infected patients. Changes occurring after HAART introduction were analysed. A negative binomial regression model established a 46% decrease of the incidence of cryptococcosis during the post-HAART era (1997-2001, n = 292) compared to the pre-HAART era (1985-1996, n = 1352). According to multivariate analysis, African origin, older age, heterosexual HIV contamination, no previous AIDS-defining illness, and no previous HIV infection diagnosis were variables independently associated with an increased risk of cryptococcosis during the post-HAART era. During the same period, the characteristics of the HIV-negative population did not change. CONCLUSIONS: Our analysis of the national surveillance identified demographic factors associated with an increased risk of cryptococcosis in the post-HAART era suggesting that failure to consult and considering oneself not at risk were determinant in the current epidemiology of HIV-related cryptococcosis in France.

Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy.

OBJECTIVE: Combination antiretroviral therapy in a subset of HIV-infected patients, here called CD4-low responders (CD4-LR), fails to produce a rapid rise in CD4 cell counts despite effective control of plasma viral load (< 50 copies/ml). The mechanism responsible for this failure was investigated. DESIGN AND METHODS: CD4-LR patients (n = 13) included in the study had been receiving stable antiretroviral therapy for > 9 months, resulting in undetectable viral load, but nontheless showed a CD4 cell count of < 200 x 106 cells/l. Samples from these patients were analysed for intracellular expression of the anti-apoptotic molecule Bcl-2 and the in vitro apoptosis of their CD4 lymphocytes. Since interleukin-2 (IL-2) induces Bcl-2 and participates in the control of lymphocyte apoptosis, we also investigated the IL-2/IL-2 receptor (IL-2R) system in these CD4-LR patients. All these investigations were performed before and after the CD4-LR patients received IL-2 therapy. RESULTS: CD4 T lymphocytes from these patients underexpressed the anti-apoptotic molecule Bcl-2 and were more susceptible to spontaneous apoptosis. Peripheral CD4 T lymphocytes from the CD4-LR patients showed a regulatory dysfunction in the IL-2R system that resulted in a lack of reactivity to IL-2. Overall, the results obtained with CD4-LR patients differed radically from those in patients undergoing successful antiretroviral therapy. Finally, an increase in Bcl-2 expression and IL-2 reactivity was observed in the CD4 T lymphocytes of CD4-LR patients receiving IL-2 immunotherapy. This correlated with a reduction in their apoptosis. CONCLUSION: Our study characterizes the defective maintenance of peripheral CD4 T lymphocytes in CD4-LR patients, probably resulting from Bcl-2 underexpression and dysregulation of the IL-2R system.

Primary cutaneous cryptococcosis: a distinct clinical entity.

Cryptococcus neoformans is an encapsulated yeast responsible for disseminated meningitis in immunocompromised hosts. Controversies persist on the existence of primary cutaneous cryptococcosis (PCC) versus cutaneous cryptococcosis being only secondary to hematogenous dissemination. Thus, we reviewed cryptococcosis cases associated with skin lesions reported in the French National Registry. Patients with PCC (n=28) differed significantly from those with secondary cutaneous cryptococcosis (n=80) or other forms of the disease (n=1866) by living area (mostly rural), age (older), ratio of men to women (approximately 1:1), and the lack of underlying disease. Evidence of PCC included the absence of dissemination and, predominantly, a solitary skin lesion on unclothed areas presenting as a whitlow or phlegmon, a history of skin injury, participation in outdoor activities, or exposure to bird droppings, and isolation of C. neoformans serotype D. Therefore, PCC is a distinct epidemiological and clinical entity with a favorable prognosis even for immunocompromised hosts.

Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy.

We report the case histories of 7 human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) who had a diagnosis of Castleman disease. All 6 patients who were treated responded to chemotherapy; immune reconstitution was observed in 5 patients, but it did not prevent relapse of Castleman disease. However, the mean duration of survival observed in this series (48 months) was most probably due to immune reconstitution resulting from receipt of HAART, which reduced the mortality associated with HIV disease.

Voriconazole treatment for less-common, emerging, or refractory fungal infections.

Treatments for invasive fungal infections remain unsatisfactory. We evaluated the efficacy, tolerability, and safety of voriconazole as salvage treatment for 273 patients with refractory and intolerant-to-treatment fungal infections and as primary treatment for 28 patients with infections for which there is no approved therapy. Voriconazole was associated with satisfactory global responses in 50% of the overall cohort; specifically, successful outcomes were observed in 47% of patients whose infections failed to respond to previous antifungal therapy and in 68% of patients whose infections have no approved antifungal therapy. In this population at high risk for treatment failure, the efficacy rates for voriconazole were 43.7% for aspergillosis, 57.5% for candidiasis, 38.9% for cryptococcosis, 45.5% for fusariosis, and 30% for scedosporiosis. Voriconazole was well tolerated, and treatment-related discontinuations of therapy or dose reductions occurred for <10% of patients. Voriconazole is an effective and well-tolerated treatment for refractory or less-common invasive fungal infections.

Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children.

OBJECTIVE: To describe the safety and efficacy of voriconazole in children treated within the compassionate release program. METHODS: Children received voriconazole on a compassionate basis for treatment of an invasive fungal infection if they were refractory to or intolerant of conventional antifungal therapy. Voriconazole was administered as a loading dose of 6 mg/kg every 12 h i.v. on Day 1 followed by 4 mg/kg every 12 h i.v. thereafter. When feasible the route of administration of voriconazole was changed from i.v. to oral (100 or 200 mg twice a day for patients weighing < 40 or > or = 40 kg, respectively). Outcome was assessed by investigators at the end of therapy or at the last visit as success (complete or partial response), stable infection, or failure, based on protocol-defined criteria. RESULTS: Sixty-nine children (ages 9 months to 15 years; median, 7 years) received voriconazole; 58 had a proven or probable fungal infection. Among these 58 patients 27 had hematologic malignancies and 13 had chronic granulomatous disease as the most frequent underlying conditions. Forty-two patients had aspergillosis, 8 had scedosporiosis, 4 had invasive candidiasis and 4 had other invasive fungal infections. The median duration of voriconazole therapy was 93 days. At the end of therapy 26 patients (45%) had a complete or partial response. Four patients (7%) had a stable response, 25 (43%) failed therapy and 4 (7%) were discontinued from voriconazole because of intolerance. Success rates were highest in patients with chronic granulomatous disease (62%) and lowest in patients with hematologic malignancies (33%). Two patients experienced treatment-related serious adverse events (ulcerated lips with rash, elevated hepatic transaminases or bilirubin). A total of 23 patients had voriconazole-related adverse events, 3 (13%) of which caused discontinuation of voriconazole therapy. The most commonly reported adverse events included elevation in hepatic transaminases or bilirubin (n = 8), skin rash (n = 8), abnormal vision (n = 3) and a photosensitivity reaction (n = 3). CONCLUSION: These data support the use of voriconazole for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy.